Background

While the direct thrombin inhibitor dabigatran etexilate is associated with less serious bleeding than warfarin, when used for the prevention of stroke in nonvalvular atrial fibrillation [1-3], life-threatening bleeding may occur. Also in case patients require urgent surgery or intervention, a specific dabigatran-reversal agent would be beneficial.
Idarucizumab is a monoclonal antibody fragment that binds dabigatran with much higher affinity than observed with thrombin [4,5]. By binding free and thrombin-bound dabigatran, idarucizumab neutralising its activity [4,5].
Administration of idarucizumab produced immediate and complete reversal of the anticoagulant effects of dabigatran in healthy young volunteers, volunteers aged 65 to 80 years, and in volunteers with mild or moderate renal impairment [6-8]. The current article presents the results of the first 90 days in a prospective cohort study (Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD)), examining the efficacy and safety of idarucizumab in patients treated with dabigatran who presented with serious bleeding (group A, n=51) or who required an urgent invasive procedure (group B, n=39). Patients received 5 mg of idarucizumab and were followed until death or for at least 1 month.

Main results

Some patients were excluded from efficacy analyses because baseline clotting tests were within the normal range (with dilute thrombin time (dTT) test: 22, ecarin clotting time test: 9).

Median maximum percentage reversal was 100% (95%CI: 100-100) in patients in group A and group B, both when assessed with dTT and ecarin clotting time.
Reversal was evident in the sample taken after the first infusion.

At 12 and 24 hours, dTT was below the upper limit of normal in 90% of group A and 81% of group B, and ecarin clotting time was below the upper limit of the normal range in 72% and 54%, respectively.

In samples obtained after the first administration of idarucizumab, the concentration of unbound dabigatran was lower than 20 ng/mL in all but one patient. At 12 hours, this was the case in 77 out of 83 patients (93%) and at 24 hours in 62 out of 78 (79%) patients.

In 36 patients in group A in whom time to cessation of bleeding could be ascertained, median investigator-reported time to cessation was 11.4 hours.
In 36 patients in group B undergoing urgent procedures, normal intra-operative haemostasis was reported in 33 (92%).

18 patients died, 10 of which were due to vascular causes (5 fatal bleeding events). Thrombotic events occurred in five patients, who did not receive antithrombotic therapy at that time. 21 Patients had serious adverse events during study participation.

Conclusion

In patients treated with dabigatran with serious bleeding or requiring urgent procedures, idarucizumab rapidly and completely reversed the anticoagulant effect in 88 to 98% of patients with elevated clotting times at baseline. Normal haemostasis could be obtained in 92% of patients undergoing a procedure, while mild-to-moderate impairment was seen in the remainder. No safety concerns were raised, including in patients who were given idarucizumab on clinical grounds who were later found to have normal clotting test results at baseline.